N-aminomethyl-2-amino(and 2-amino-methyl)-2-heterocyclic-thioacetamides

ABSTRACT

The compounds are N-aminomethyl-2-amino(and 2-aminomethyl)-2heterocyclic-thioacetamides which are inhibitors of gastric acid secretion.

United States Patent 91 Brenner et al.

[ Dec. 10, 1974 N-AMINOMETHYL-2-AMINO(AND Z-AMINO-METHYL)-2-HETEROCYCLIC- THIOACETAMIDES Inventors: L. Martin Brenner, Upper Darby;

Bernard Loev, Broomall, both of Pa.

Assignee: Smithkline Corporation,

Philadelphia, Pa.

Filed: June 26, 1972 Appl. No.2 266,024

[5 6} References Cited UNITED STATES PATENTS 3,686,190 8/1972 Malen Bt al. 260/294.8 E 3,726,878 4/1973 Kanai et al..... 260/294.8 E 3,740,409 6/1973 Brenner et al. 260/294.8 E 3,749,728 7/1973 Loev 260/294.8 E

FOREIGN PATENTS OR APPLICATIONS 2,100,970 3/1972 France Primary Examiner-G. Thomas Todd Attorney, Agent, or Firm-Keps, Joan S.; Richard D. Foggio; William H. Edgerton [57] ABSTRACT The compounds are N-aminomethyl-2-amino(and 2- aminomethyl)-2-heterocyclic-thioacetamides which are inhibitors of gastric acid secretion.

4 Claims, No Drawings N-AMINOMETHYL-2-AMINO(AND or 1 and R is dimethylamino or m is l and R is mor- 2-AMINO:ME I:YL)-2-1-1ETEROCYLIC- pholino, and R is diethylamino, pyrrolidino or mor- THIOACETAMIDES v pholino.

A particularly advantageous compound ofthis inven- 5 tion is 3-morpholino-N-morpholinomethyl-2-(2- pyridyl)-thiopropanamide. a

The compounds of this invention produce inhibition This invention relates to new N-aminomethyl-2- amino-(and Z-aminomethyl)-2-heterocyclicthioacetamides having pharmacological activity. In Ramcular these Compounds mhlblt gasmc Seem of gastric acid secretion. This activity is demonstrated tlonby administration topylorus ligated rats at doses of The compounds of thls "Wentlon are represented about 10 to about 50 mg./kg. orally. Also, this activity the followmg formulai is demonstrated by administration to chronic gastric fistula rats; (Brodie et aL, Amer. J. Physiol. FORMULA 202:812-814, 1962) at doses of about 30 to about 50 mg./l g. orally. In these procedures, compounds which R -fill-l-c-Nli-Cli -R produce an increase in the gastric pH or a decrease in the volume of gastric juice or both are considered acl tive. I 2 These compounds shown antiulcer activity in the rein which: straint-stress method in which an oral administration to m is O or 1; rats these compounds inhibit the development of ex- R is 2-pyridyl, Z-pyrimidyl, 4-pyrimidyl, Z-pyrazinyl, perimental ulcers.

2-pyrrolyl, 2-quinolyl, 2-thia2olyl or 4-thiazolyl; The compounds of this invention are prepared as fol-- and lows:

R -YI-FC-NH C11 0 l-l-R R ?H-CNH-CH -R R and R are di-lower alkylamino, N-lower alkyl-N- The terms m, R R and R are as defined above.

S l l R I ph ny p p in pyrr li in m rpholino The terms, m, R R and R are as defined above and or N-lower alkylpiperazino. R and R are the same.

This invention also includes pharmaceutically ac- According to precedure I, a 2-amino(0r 2- eeptable acid addition salts of the compounds of Foraminomethyl)-2-heterocyclic-thioacetamide is reacted mula I. with formaldehyde and an amine. The reaction is pref- The pharmacologically active compounds of this inerably carried out in an organic solvent, such as a lower vention have the basic structure of Formula I. Howalkanol, for example methanol. The reaction is carried ever, it is apparent to one skilled in the art that well out at about -40C. to about 90C.

known nuclear substituents such as lower alkyl, lower According to procedure II, a heterocyclic thioacetaalkoxy or halogen may be incorporated on the heteromide is reacted with two molar equivalents of formalcyclic rings of R and the phenyl rings. These comdehyde and two molar equivalents of an amine to give pounds are used as are the parent compounds. compounds of this invention in which m is l and R and Preferred compounds of this invention are repre- R are the same.

sented by Formula I in which m is O or 1 and R is di- The 2-amino(or 2-aminomethyl)-2-heterocyclicmethylamino, diethylamino, piperidino or pyrrolidino thioacetamide starting materials are prepared by the or m is l and R is morpholino, and R is di-lower alkylfollowing procedures.

amino, piperidino, pyrrolidino or morpholino. The terms R andR are as defined above and R is an Most preferably, in the compounds of Formula I, R alkali metal. is pyridyl. According to the above procedure, a heterocyclic- Advantageous compounds of this invention are repcarboxaldehyde, an amine and an alkali metal cyanide resented by Formula I in which R, is Z-pyridyl, mis 0 are reacted, preferably in the presence of acid, to give a 2-amino-2heterocyclic-acetonitrile which is converted to a 2-amino-2heterocyclic-thioacetamide by reacting with hydrogen sulfide in the presence of a base such as an amine or by reacting with ammonium po1y- The- 2-aminomethyl-2heterocycliothioacetamide starting materials are prepared by reacting a Z-heterocyclic-thioacetamide, Z-heterocyclicacetamide, or Z-heterocyclic-acetonitrile with an equimolar amount of formaldehyde and an equimolar amount of an amine to give the corresponding 2- aminomethyl compounds and where the intermediate is a 2-aminomethyl-2heterocyclic-acetamide, reacting with phsophorus pentasulfide to give the corresponding thioacetamide and where the intermediate is 2- aminomethyl-Z-heterocyclic-acetonitrile, reacting with hydrogen sulfide in the presence of a base such as an amine or by reacting with ammonium polysulfide to give the corresponding thioacetamide.

The pharrnaceutically acceptable, acid addition salts of the compounds of Formula 1 are formed with organic and inorganic acids by methods known to the art. For example, the base is reacted with an organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or in aqueous immiscible solvent, such as.

ethyl ether or chloroform, with the desired salt separating directly. Exemplary of the salts which are included in this invention are maleate, fumarate, succinate, oxalate, benzoate, methanesulfonate, ethanedisulfonate, benzenesulfonate, acetate, propionate, tartrate, citrate, hydrochloride, hydrobromide. sulfate, sulfamate. phosphate and nitrate salts.

The compounds of this invention are administered internally either parenterally, rectally or, preferably, orally in an amount to produce the desired biological activity.

Preferably, the compounds are administered in conventional dosage forms prepared by combining an appropriate dose of the compound with standard pharmaceutical carriers.

The pharmaceutical carrier may be for example a solid or a liquid. Exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia or cocoa butter. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm. Exemplary of liquid carriers are syrup, peanut oil, olive oil, sesame oil, propylene glycol, polyethylene glycol (mol. wt.

200-400) and water. The carrier or diluent may in clude a time delay material well known to the art such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed, for example the preparation may take the form of tablets, capsules, powders, suppositories, troches, lozenges, syrups, emulsions, sterile injectable liquids or liquid suspensions or solutions.

The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing. granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The terms lower alkyl" and lower alkoxy where used herein denote groups having 1-4 carbon atoms and,halogen" denotes chloro, bromo or fluoro.

The following examples are not limiting but are illustrative of the compounds of this invention and processes for their preparation.

EXAMPLE 1 Z-(Z-Pyridyl)thioacetamide (0.7 g., 0.0046 mole) is dissolved in 10 m1. of methanol. The solution is cooled to about -40C. and 1.0 g. (0.012 mole) of morpholine and 0.9 g. (0.012 mole) of 37% aqueous formaldehyde solution are added simultaneously. The mixture is allowed to stand at 20C. for 48 hours, then the solvent is removed under reduced pressure (no heat is applied). The viscous liquid is chromatographed on an acetone slurried Florisil (magnesia-silica gel) column. The yellow eluant is collected, the solvent removed and the residual liquid applied to an ethyl acetate slurried Florisil (magnesia-silica gel) column. Again the yellow eluant is concentrated and the residual viscous liquid is triturated with ethyl acetate and left at 20C. for 18 hours. The resulting precipitate is filtered and washed with cold ethyl acetate to give S-morpholino-N- morpho1inomethyl-2-( 2-pyridy1)thiopropanamide.

EXAMPLE 2 To cold 2-pyridinecarboxaldehyde pyridinecarboxaldehyde (21.4 g., 0.2 mole) is added dimethylamine (22.5 g. of a 40% aqueous solution, 0.2 mole) and the solution is neutralized with concentrated hydrochloric acid. To the stirred neutralized solution is added 14.4 g. (0.22 mole) of potassium cyanide. The mixture is stirred overnight, then diluted with water, transferred to a separatory funnel and repeatedly extracted with chloroform. The combined chloroform extracts are washed three times with water, once with brine and dried over magnesium sulfate. The mixture is filtered, the solvent is removed under reduced pressure and methanol is added to the residue. The mixture is allowed to stand at 20C. for 18 hours, then filtered. The filtrate is concentrated and distilled in vacuo to give 2-dimethylamino-2-(2-pyridyl)-acetonitrile.

2-Dimethylamino-2-(2-pyridyl)acetonitrile (11.4 g., 0.07 mole) is dissolved in 200 ml. of dry pyridine containing 5 m1. of anhydrous triethylamine. Hydrogen sultide is bubbled into the stirred solution for 7 hours and the solution is then stirred for 17 hours. This procedure is repeated for 5 days. Then the mixture is stirred for an additional 48 hours. The solvent is then removed under reduced pressure and the residue is recrystallized from ethanol to give Z-dimethylamino-Z-(Z- pyridyl)thioacetamide, m.p. 133C. (dec.).

To a solution of 1.8 g. (0.0091 mole) of 2-dimethylamino-2-(2-pyridyl)thioacetamide in 25 ml. of methanol is added 0.9 g. (0.010 mole) of morpholine in 2ml. of methanol and 0.9 g. (0.01 1 mole) of 37% aqueous formaldehyde solution in 2 ml. of methanol. The resulting solution is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and ether is added to the residue. The mixture is cooled at 20C. for four hours and then filtered. The solvent is evaporated from the filtrate to give Z-dimethylamino- N-morpholinomethy1-2-(2-pyridy1)-thioacetamide.

EXAMPLE 3 Hydrogen sulfide is bubbled into a stirred solution of 10.0 g. (0.048 mole) of 2morpholino-2-(2-pyridyl)- acetonitrile, dissolved in 200 ml. of dry pyridine containing 5 ml. of anhydrous triethylamine, for seven hours and then the mixture is stirred for 17 hours. Hydrogen sulfide is again bubbled into the stirred mixture and the mixture is again stirred for 17 hours. Then the solvent is removed under reduced pressure and the residue is recrystallized from ethanol to give 2- morpholino-2-(2-pyridyl)thioacetamide, m.p.

l72175C. (dec.).

2-Morpholino-2-(2-pyridyl)thioacetamide (1.0 g., 0.0042 mole) is dissolved with heating in 30 ml. of 5 methanol. To the warm solution is added 1.0 g. (0.012 mole) of morpholine and 1.84 g. (0.022 mole) of 37 aqueous formaldehyde solution. The resulting solution is refluxed three hours and then stirred for 17 hours. The solvent is evaporated and the residue is recrystallized from methanol/ether to give 2-morpholino-N- morpholinomethyl-2-(2-pyridyl)thioacetamide, m.p. l44l47C. (dec.).

EXAMPLE 4 By the procedure of Example 1, using in place of morpholine, the following amines:

pyrrolidine piperidine l-methylpiperazine diethylamine the products are, respectively:

3-pyrrolidino-N-pyrrolidinomethyl-2-(2-pyridyl)- thiopropanamide 3-piperidino-N-piperidinomethyl-2-( 2-pyridyl)- thiopropanamide 3-(4-methylpiperazino)-N-(4- methylpiperazinomethyl)-2-(2-pyridyl)thiopropanamide 3-diethylamino-N-diethylaminomethyl-2-( 2- pyridyl)-thiopropanamide.

EXAMPLE 5 EXAMPLE 6 By the procedure of Example 2, using in place of 2- dimethylamino-2-(2-pyridyl)acetonitrile, the following acetonitriles:

2-dicthylamino-Z-t2-pyridyl)acetonitrile 2-pyrrolidino-2(Z-pyridyl)acctonitrilc 2-piperidino-2-('Z-pyridyl)acetonitrile 2-dimethylamino-2-(2-quinolyl)acetonitrile Z-piperidino- 2-( 2-quinolyl)acetonitrile the products are, respectively:

Z-diethylamino-N-morpholinomethyl-2-(2-pyridyl)- thioacetamide 6 N-morpholinomethyl-Z-pyrrolidino-2-( 2-pyridyl thioacetamide N-morpholinomethyl-2-piperidino-2-( 2-pyridyl thioacetamide 2-dimethylamino-N-morpholinomethyl-2-( 2- quinolyl )-thioacetamide N-morpholinomethyl-2-piperidino-2-( 2-quinolyl thioacetamide.

EXAMPLE 7 To 27.0 g. of 2-pyrimidinecarboxaldehyde and 11.3 g. of dimethylamine (neutralized with hydrochloric acid) is added, with stirring and cooling, l7.9 g. of potassium cyanide in a small amount of water. The mixture is allowed to stand overnight and ether is added. Concentrating and distilling the residue gives 2- dimethylamino-2-( 2--pyrimidyl)-acetonitrile.

Using 2-dimethylaminol2-(2-pyridyl)acetonitrile in the procedure of Example 2 gives 2-dimethylamino-N- morpholinomethyl-2-(2-pyrimidyl)thioacetamide.

EXAMPLE 8 By the procedure of Example 2, using the following carboxaldehydes in place of Z-pyridinecarboxaldehyde:

4-pyrimidinecarboxaldehyde 2-pyrazinecarboxaldehyde 2-pyrrolecarboxaldehyde 2-thiazolecarboxaldehyde 4-thiazolecarboxaldehyde the products are, respectively:

2-dimethylamino-N-morpholinomethyl-2-( 4- pyrimidyl)-thioacetamide 2-diemthylamino-N-morpholinomethyl-Z-(2- pyrazinyl )-thioacetamide 2-dimethylamino-N-morpholinomethyl-2-( 2-pyrrolyl)-thioacetamide 2-dimethylamino-N-morpholinomethyl-2-( 2- thiazolyl )-thiacetamide 2-dimethylamino-N-morpholinomethyl-2-(4- thiazolyl )-thioacetamide.

EXAMPLE 9 By the procedure of Example 2, using diethylamine in place of dimethylamine, the product is 2- diethylamino-N-morpholinomethyl-2-( 2- pyridyl)thioacetamide.

Similarly, using dipropylamine, the product is 2- dipropylamino-N-morpholinomethyl-2-(2- pyridyl )thioacetamide.

By the same procedure, using dibutylamine, the product is 2-dibutylamino-N-morpholinomethyl-2-(2- 5 pyridyl)-thioacetamide.

EXAMPLE 10 By the procedure of Example I, using in place of morpholine the following l-lower alkylpiperazines:

l-ethylpiperazine l-propylpiperazine l-butylpiperazine the products are. respectively:

3-(4-ethylpiperazino)-N-(4-ethylpiperazinomethyl)- 2-(2-pyridyl)thiopropanamide 3-(4-propylpiperazino)-N-(4- propylpiperazinomethyl )-2-( 2-pyridyl )thiopropanamide 3-( 4-butylpiperazino )-N 4-butylpiperazinomethyl 2-( 2-pyridyl )thiopropana mide.

EXAMPLE l 1 By the procedure of Example 2, using the following l-lower alkylpiperazines in place of dimethylamine:

EXAMPLE 12 A solution of 3.0 g. (0.019 mole) of 2-(2-pyridyl)- thioacetamide in 40 ml. of anhydrous methanol is treated at -40C. with l.7 g. (0.0l9 mole) of morpholine in ml. of methanol and 1.6 ml. of 37% formalin solution. The resulting mixture is kept at C. for 36 hours.

The solvents are evaporated in vacuo at 25C. and the residue is triturated 3 times with ether in the cold. The ether is decanted and the residue is recrystallized from acetone/hexane to give 3-morpholino-2-(2pyridyl thiopropanamide.

The above prepared 3-morpholino-2-(2-pyridyl)- thiopropanamide is reacted with pyrrolidine and formaldehyde in methanol by the procedure of Example 2 to give B-morpholino-N-pyrrolidinomethyl-2-(2- pyridyl)thiopropanamide.

By the same procedure, using the following compounds in place of pyrrolidine:

dimethylamine diethylamine piperidine l-methylpiperazine the products are, respectively:

N-dimethylaminomethyl- 3-morpholino-2-( 2- pyridyl)-thiopropanamide N-diethylaminomethyl-3-morpholino-2-(2-pyridyl)- thiopropanamide 3morpholino-N-piperidinomethyl-2-92-pyridyl)- thiopropanamide N-( 4-methylpiperazinomethyl )-3-morpholino-2-( 2- pyridyll-thiopropanamide.

EXAMPLE 13 One gram of 3-morpholino-N-morpholinomethyl- 2-(2-pyridyl)thiopropanamide in ethanol is treated with ethereal hydrogen chloride and the solvents are removed under reduced pressure to give 3-morpholino- N-morpholinomethyl-2-( 2-pyridyl )thiopropanamide trihydrochloride.

Similarly, using ethereal hydrogen bromide, the hydrobromide salt is prepared.

EXAMPLE l4 2-Dimethylamino-N-morpholinomethyl-2-(2- pyridyl)-thioacetamide in ethanol is treated with an equimolar amount of oxalic acid in ethanol to give, after removing the solvent under reduced pressure, 2- dimcthylamino-N-morpholinomethyl-2-( 2- pyridyl)thioacetamide oxalate.

Similarly, using maleic acid, Z-dimethylamino-N- morpholinomethyl-2-(2-pyridyl)thioacetamide male ate is prepared.

In the same manner, using citric acid, 2-

dimethylamino-N-morpholinomethyl-2-(2- pyridyl)thioacetamide citrate is prepared.

EXAMPLE 15 Using N-methylaniline in place of moprholine in the procedure of Example 1, the product is 3-(N-methyl-N- phenylamino-N-(N-methyl-N-phenylaminomethyl)-2- (Z-pyridyll-thiopropanamide.

Similarly, using N-ethylaniline, the product is 3-(N ethyl-N-phenylamino )-N-( N-ethyl-N- phenylaminomethyl )-2-(2-pyridyl )thiopropanamide.

By the same procedure, using the appropriate N- lower alkylanilines, the products are B-(N-propyl-N- phenylamino)-N-(N-propyl-N-phenylaminomethyl)-2- (2-pyridyl )-thiopropanamide and 3 -(N -butyl-N- phenylamino)-N-(N-butylN-phenylaminomethyl)2- (Z-pyridyl )thiopropanamide.

EXAMPLE 16 Using N-methylamiline in place of dimethylamine in the proceudre of Example 2, the product is 2-(N- methyl-N-phenylamino)-N-morpholinomethyl-2-(2 pyridyl )thioacetamide.

Similarly, using the appropriate N-lower alkylanilines, the corresponding N-ethyl, N-propyl and N-butyl compounds are prepared.

EXAMPLE 17 By the procedure of Example 2, using in place of morpholine, the following amines:

pyrrolidine piperidine l-methylpiperazine diethylamine the products are, respectively:

Z-dimethylamino-N-pyrrolidinomethyl-2-(2 pyridyl )-thioacetarnide 2-dimethylamino-N-piperidinomethyl-2-(2-pyridyl)- thioacetamide 2-dimethylamino-N-(4-methylpiperazinomethyl)-2- (Z-pyridyl )thioacetamide 2-dimethylamino-N-diethylaminomethyl-2-(pyridyl)- thioacetamide. What is claimed is: l. A compound of the formula:

Epm

in which:

m is 0 or 1; R is Z-pyridyl; and R and R are di-lower alkylamino, N-lower alkyl-N- phenylamino, piperidino, pyrrolidino or morpholino 9 10 or a pharmaceutically acceptable acid addition salt 3. A compound of claim 1 in which m is O or 1 and thereof. R is dimethylamino or m is 1 and R is morpholino,

2. A compounds of claim 1 in which m is or 1 and and R is diethylamino, pyrrolidino or morpholino.

R is dimethylamino, diethylamino, piperidino or pyr- 4. A compound of claim 1, said compound being 3- rolidino or m is l and R is morpholino, and R is di- 5 morpholino-N-morpholinomethyl-2-(2-pyridyl)thiolower alkylamino, piperidino, pyrrolidino or morphopropanamide. lino. 

1. A COMPOUND OF THE FORMULA:
 2. A compounds of claim 1 in which m is 0 or 1 and R2 is dimethylamino, diethylamino, piperidino or pyrrolidino or m is 1 and R2 is morpholino, and R3 is di-lower alkylamino, piperidino, pyrrolidino or morpholino.
 3. A compound of claim 1 in which m is 0 or 1 and R2 is dimethylamino or m is 1 and R2 is morpholino, and R3 is diethylamino, pyrrolidino or morpholino.
 4. A compound of claim 1, said compound being 3-morpholino-N-morpholinomethyl-2-(2-pyridyl)thiopropanamide. 